Methods and devices for quantitative analysis of x-ray images

ABSTRACT

The present invention relates to network enabled analysis of x-ray images. Also described are devices comprising calibration phantoms; methods of using these devices; methods of formulating databases containing information regarding x-ray images; the databases themselves; and methods of manipulating the information and databases.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of U.S. Ser. No. 09/942,528,filed Aug. 29, 2001, which in turn claims the benefit of U.S.Provisional patent application Ser. No. 60/228,591, filed 29 Aug. 2000,both of which applications are incorporated herein by reference in theirentirety.

TECHNICAL FIELD

The present invention is in the field of radiographic imaging andanalysis thereof. In particular, network enabled analyses and analysistechniques are described. Also described are devices comprisingcalibration phantoms and methods of using these devices.

BACKGROUND

X-rays and other radiographic analysis are important diagnostic tools.Furthermore, it is common practice to transmit x-ray images via localand long-distance networks. Current technology, however, does not allowfor the accurate determination of quantitative information contained inthe x-ray such as the density of an anatomic structure when x-ray imagesare transmitted in a network environment.

Calibration references (also known as calibration phantoms) for use inimaging technologies have also described. See, e.g., U.S. Pat. Nos.5,493,601 and 5,235,628. U.S. Pat. No. 5,335,260 discloses a calibrationphantom representative of human tissue containing variableconcentrations of calcium that serves as reference for quantifyingcalcium, bone mass and bone mineral density in radiography and CTimaging systems. However, currently-available calibration phantoms arenot always accurate, due to both the effect of structures or materialsthat project on or with the calibration phantom and, additionally, tothe fact that one or more regions of the calibration phantom do notalways appear on the x-ray image.

Thus, there remains a need for methods for quantitative assessment ofinformation contained in x-ray images such as the density of an anatomicstructure in a network environment. There also remains a need fordevices and methods that include dependable and accurate calibrationphantoms.

SUMMARY

The present invention meets these and other needs by providingcompositions and methods that allow for the analysis of x-ray images ina network environment. Also provided are x-ray assemblies comprisingaccurate calibration phantoms including, in particular, calibrationphantoms which act as references in order to determine bone mineraldensity from an x-ray image.

In one aspect, the invention includes a method for deriving quantitativeinformation from an x-ray image in a network environment comprising,providing a local computer for transmitting the x-ray image, providing aremote computer for receiving the x-ray image and providing a computerprogram to analyze and extract quantitative information from the x-rayimage. In certain embodiments, the quantitative information isdensitometric information, for example bone mineral density or densityof selected soft-tissues or organs. Alternatively, the quantitativeinformation is information on the morphology of a structure, for exampleinformation on the two-dimensional arrangement of individual componentsforming said structure or information on the three-dimensionalarrangement of individual components forming said structure. In any ofthe methods described herein, the structure can be bone and theinformation can be, for example, information on trabecular thickness,trabecular spacing and/or estimates of the two- or three-dimensionalarchitecture of the trabecular network. Further, in any of the methodsdescribed herein, quantitative information can be derived with use of anexternal standard, for example a calibration phantom of known x-raydensity. (e.g., a calibration phantom is included with the structure tobe imaged on the x-ray image).

In other embodiments, the quantitative information derived from thex-ray image includes one or more parameters relating to the acquisitionof the x-ray image (e.g., x-ray tube voltage, x-ray energy, x-ray tubecurrent, film-focus distance, object-film distance, collimation, focalspot size, spatial resolution of the x-ray system, filter technique,film focus distance, correction factor(s) or combinations thereof), forinstance to improve the accuracy of the quantitative information. Thex-ray acquisition parameters can be transferred over the network priorto, simultaneously or after transmission of the x-ray image.Furthermore, one or more of the x-ray acquisition parameters can beentered either manually or, alternatively, automatically into acomputer.

In another aspect, a method for measuring quantitative information in anx-ray image in a network environment is provided. In certainembodiments, the method comprises transmitting an x-ray image from alocal computer to a remote computer and obtaining quantitativeinformation from the x-ray image using a computer program. In certainembodiments, one or more internal standard is provided in (or with) thex-ray image or the computer program. The internal standard can be, forexample, density of a tissue of a human (e.g., subcutaneous fat, bone,muscle), air surrounding a structure or combinations of tissue and airdensity. In other embodiments, one or more external standards areprovided in (or with) the x-ray image or computer program. The at leastone external standard (e.g., calibration phantom can be temporarily orpermanently physically connected to the x-ray film with use of anattachment mechanism, for example a mechanical attachment mechanism suchas Velcro or adhesive. Additionally, the at least one external standardcan be integrated into the film and/or film holder, for example byincluding a material of known x-ray density between two of the physicallayers of the x-ray film or by including a material of know x-raydensity within one of the physical layers of the x-ray film.

In other aspects, any of the methods described herein further comprisethe steps of generating a diagnostic report based on the quantitativeinformation and, optionally, sending the diagnostic report (for exampleto a physician). Such reports can be generated using computer programs,for example programs on the remote computer. The diagnostic report caninclude, for example, information on a patient's state of health (e.g.,bone mineral density status such as osteoporosis and/or information onfracture risk). Other disease states can also be analyzed from x-rayimages using the teachings described herein. In certain embodiments,these methods further comprise generating a bill (accounting of charges)for the recipient of the diagnostic report. The bill can include chargesfor generating the report, profession fees, technical fees or the like.The bill can be printed and transmitted by mail or by fax to therecipient or the bill can be electronically transmitted. The recipientcan be a physician, a subject, a patient, the patient's employer, ahealth maintenance organization, health insurance provider, a governmentagency, or government representative. The bill can also be divided andvarious portions thereof sent to multiple recipients. In certainembodiments, the bill is generated using a computer program on theremote computer.

In another aspect, the invention includes a method of formulating one ormore x-ray image data databases, said method comprising collecting x-rayimage data (e.g., densiometric information) from one or more subjects,formulating said one or more data databases by associating each of saiddata points with one or more data attributes (e.g., age of subject,weight of subject, height of subject, disease state, etc. The data canbe collected using x-ray imaging techniques, for example by usingdigital or digitized x-ray images. In certain embodiments, the data isfrom a single subject while in other embodiments, the data is from twoor more subjects. In other embodiments, the methods further comprisecompiling multiple databases from each database where the data pointsare collected from a single individual and the data points for eachsingle individual are associated with one or more relevant dataattributes.

In any of the methods described herein, the quantitative information canbe densitometric information, for example bone mineral density ordensity of selected soft-tissues or organs. Alternatively, thequantitative information is information on the morphology of astructure, for example information on the two-dimensional arrangement ofindividual components forming said structure or information on thethree-dimensional arrangement of individual components forming saidstructure. In any of the methods described herein, the structure can bebone and the information can be, for example, information on trabecularthickness, trabecular spacing and/or estimates of the two- orthree-dimensional architecture of the trabecular network. Furthermore,the information can be encrypted in any of the methods described herein(e.g., to hide the subject's name or other demographic information fromunauthorized users).

Furthermore, in any of the methods described herein, the x-ray image canbe derived from x-ray film, for example using a phosphorous platesystem. Preferably, the image is digitized, for example, the image maybe acquired digitally (e.g., using a selenium or silicon detectorsystem) or digitized using a scanning unit.

In another aspect, the invention includes databases made by any of themethods described herein, for example by formulating data pointscollected from x-ray images. In certain embodiments, the data points areassociated with one or more relevant data attributes.

In another aspect, a method of manipulating an x-ray image datadatabase, comprising providing any of the databases comprising datapoints and data attributes described herein; and manipulating said datapoints via said attributes associated with said data points to determinerelationships between said data points and said attributes.

In another aspect, the invention includes an x-ray assembly fordetermining bone mineral density comprising an x-ray film holder; x-rayfilm and a calibration phantom comprising at least one marker, forexample, a line, or other geometric pattern (e.g., circles, stars,squares, crescents, ovals, multiple-sided objects, irregularly shapedobjects or combinations of any of these shapes) positioned in an area ofknown density and wherein the calibration phantom projects free of bonetissue. The calibration phantom can be attached to the x-ray film, thefilm holder and/or the detection system. The attachment can be permanent(e.g., integral to the film such as between two physical layers of thefilm or within one layer of the film, and/or integral to the film holderor detector) or temporary (e.g., via a mechanical or other attachmentmechanism such as Velcro, adhesive or the like). Thus, in certainembodiments, the calibration phantom is reusable and/or can besterilized between uses. In certain embodiments, the assembly is adental x-ray assembly. In any of the x-ray assemblies described herein,the calibration phantom can be shaped, for example, as a stepwedge or asa plurality of fluid-filled chambers of known densities.

In certain aspects, a wedge-shaped calibration phantom is used toprovide reference measurements to express the density of an anatomicstructure in terms of thickness of the phantom material. For example,described herein are methods of generating a calibration curvedescribing the relationship between measured attenuation and materialthickness wherein the data points making up the curve are derived fromthe image of the phantom. In certain embodiments, the wedge-shapedcalibration phantom has a length L and a linear change from a maximumthickness T to thickness 0 over the length (e.g., the calibrationphantom has two ends—one marking the thinnest point and one thethickest, where thickness varies linearly between the two ends). Inthese embodiments, each point X in the image of the wedge at distance Dfrom the thin end of the wedge results in a point (T*L/D, G) of thecalibration curve, where T*L/D is the thickness of the wedge at X and Gthe attenuation at X.

Alternatively, calibration curves can also be generated when thedistance D is unknown, for example if the calibration wedge variesnon-linearly over its length or both ends of the phantom cannot beproperly identified in the image. In certain embodiments, the shape ofthe expected entire calibration curve is determined, and the part of thecurve that can be calculated from the identified regions of thecalibration wedge is fitted to the expected curve. For a knownattenuation of a particular anatomic structure, the correspondingthickness value is determined with use of said calibration curve.

Furthermore, calibration curves generated from both linear andnon-linear phantoms can be further manipulated, for example to translatethickness data into concentration (e.g., calcium concentration). Incertain embodiments, the image of an aluminum step wedge and acalibration curve expressing thickness is translated into units ofcalcium concentration by including samples of varying calciumconcentration in the image. Using this second calibration curve, valuesexpressed in aluminum thickness can be converted into units of calciumconcentration.

In still further embodiments, a reference calibration curve can begenerated, for example by averaging a plurality of calibration curvesobtained by any of the methods described herein (e.g., thickness and/orconcentration curves). Reference calibration curves find use in analysisof images that do not have their own phantoms or other standards.

In yet another aspect, the invention includes methods of obtainingaccurate bone mineral density information using any of the calibrationphantoms and/or methods described herein. Thus, in certain embodiments,the methods comprise positioning any of the calibration phantomsdescribed herein such that x-rays pass through a subject and thecalibration phantom simultaneously, wherein the calibration phantomprojects free of materials that alter its' apparent density; creating animage of the phantom and the portion of the subject's anatomy; andcomparing the image of the phantom and the subject's anatomy todetermine bone mineral density of the subject. The x-ray image can be,for example, a dental x-ray. Any of the methods described herein can beperformed on a computer, in a network environment, or manually.

Another aspect of the invention is a kit for aiding in assessing thecondition of bone in a subject, which kit comprises a software program,which that when installed and executed on a computer reads an x-rayimage (e.g. a digital or digitized dental x-ray) and produces a computerreadout showing bone mineral density. Any of the kits described hereincan also include a calibration phantom, x-ray film, x-ray film holdersand computer programs (e.g., software) for displaying and/or generatinga bill for the readout regarding bone mineral density.

In yet another aspect, methods of diagnosing osteoporosis in a subjectare provided, for example using any of the kits, methods and/or devicesdescribed herein. In certain embodiments, the methods of diagnosingosteoporosis in a subject comprise using a computer program to analyzebone mineral density of an x-ray image and comparing the bone mineraldensity value obtained from the image with a reference standard orcurve, thereby determining if the subject has osteoporosis. In certainembodiments, the x-ray image includes a calibration phantom, for examplea calibration phantom as described herein. In other embodiments, areference calibration curve can be used to analyze the image.

In still further aspects, methods of assessing bone mineral density areused to provide suitable treatment for a subject in need thereof. Forinstance, using any of the methods, kits, and/or devices describedherein, the presence of osteoporosis in a subject can be diagnosed andthat subject provided with appropriate therapy (e.g., one or moreanti-resorptive agents and/or one or more anabolic agents).Additionally, over time, the methods described herein can be used toassess the efficacy of the selected treatment. Thus, in certainembodiments, diagnosis and/or treatment of osteoporosis are achieved ina network-enabled environment.

These and other embodiments of the subject invention will readily occurto those of skill in the art in light of the disclosure herein.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 depicts an example of network enabled quantitative x-ray analysisuseful in monitoring osteoporosis.

FIG. 2 depicts an exemplary dental x-ray film holder. The film holderincludes a calibration phantom.

FIG. 3 depicts another exemplary dental x-ray film holder. The filmholder includes a calibration phantom.

FIG. 4 depicts an exemplary embodiment in which a calibration phantom isattached to a dental x-ray film holder.

FIG. 5 depicts an exemplary embodiment in which a calibration phantom isattached to x-ray film.

FIG. 6 depicts an exemplary embodiment in which a calibration phantom isintegrated into a film cover.

FIG. 7 depicts an exemplary embodiment in which a calibration phantom isintegrated into a detector system.

FIG. 8 depicts exemplary measurement sites in a dental x-ray that can beused as an intrinsic standard to calibrate the image.

FIG. 9 depicts exemplary measurement sites in a dental x-ray that can beused as an intrinsic standard to calibrate the image.

FIG. 10. panels A to C, depict exemplary wedge-shaped calibrationphantoms as described herein. FIG. 10. panel A, is a front view of anexemplary calibration phantom. FIG. 10. panel B, is an overview of anexemplary calibration phantom in which the thickness of the calibrationphantom varies linearly along the length. FIG. 10. panel C, is anoverview of an exemplary calibration phantom in which the thickness ofthe calibration phantom varies non-linearly along the length.

DETAILED DESCRIPTION

Before describing the present invention in detail, it is to beunderstood that this invention is not limited to particular formulationsor process parameters as such may, of course, vary. It is also to beunderstood that the terminology used herein is for the purpose ofdescribing particular embodiments of the invention only, and is notintended to be limiting.

The practice of the present invention employs, unless otherwiseindicated, conventional methods of database storage and manipulation,within the skill of the art. Such techniques are explained fully in theliterature. See, e.g., Numerical Mathematical Analysis, Third Edition,by J. B. Scarborough, 1955, John Hopkins Press, publisher; SystemAnalysis and Design Methods, by Jeffrey L. Whitten, et al., FourthEdition, 1997, Richard D. Irwin, publisher; Modem Database Management,by Fred R. McFadden, et al., Fifth Edition, 1999, Addison-Wesley Pub.Co., publisher; Modem System Analysis and Design, by Jeffery A. Hoffer,et al., Second Edition, 1998, Addison-Wesley Pub. Co., publisher; DataProcessing: Fundamentals, Design, and Implementation, by David M.Kroenke, Seventh Edition, 2000, Prentice Hall, publisher; Case Method:Entity Relationship Modelling (Computer Aided Systems Engineering), byRichard Barker, 1990, Addison-Wesley Pub Co., publisher.

All publications, patents and patent applications cited herein, whetherabove or below, are hereby incorporated by reference in their entirety.

It must be noted that, as used in this specification and the appendedclaims, the singular forms “a”, “an”, and “the” include plural referentsunless the content clearly dictates otherwise. Thus, for example,reference to “a calibration phantom” includes a one or more suchphantoms.

Definitions

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which the invention pertains. Although any methods andmaterials similar or equivalent to those described herein can be used inthe practice for testing of the present invention, the preferredmaterials and methods are described herein.

The term “subject” encompasses any warm-blooded animal, particularlyincluding a member of the class Mammalia such as, without limitation,humans and nonhuman primates such as chimpanzees and other apes andmonkey species; farm animals such as cattle, sheep, pigs, goats andhorses; domestic mammals such as dogs and cats; laboratory animalsincluding rodents such as mice, rats and guinea pigs, and the like. Theterm does not denote a particular age or sex and, thus, includes adultand newborn subjects, whether male or female.

“Parameter” refers to an arbitrary constant or variable so appearing ina mathematical expression that changing it gives various cases of thephenomenon represented (McGraw-Hill Dictionary of Scientific andTechnical Terms, S. P. Parker, ed., Fifth Edition, McGraw-Hill Inc.,1994). A parameter is any of a set of properties whose values determinethe characteristics or behavior of something.

A “data point”, generally, is a numeric value which corresponds to aphysical measurement (an “acquired” datum or data point) or to a singlenumeric result calculated or derived from one or more acquired datapoints (a “calculated” or “derived” datum or data point). Derived datainclude, but are not limited to, derived quantities from original data,such as, rate and/or magnitude of change, slope of a line (e.g., asdetermined by regression analysis), an intercept (e.g., as determined byregression analysis), and correlation coefficients.

“Data tags,” also referred to as “attributes” of a data point, arevarious characteristics of the particular data point with which they areassociated. For example, data points comprising x-ray information(and/or bone mineral density) are associated with a number ofattributes, e.g., the date and time the image was taken; certainidentification related to the particular subject from which themeasurement was made (e.g., demographic information such as theparticular user's sex, age, weight or race; medical information e.g.,the medications used by the subject and/or type of disease suffered bythe subject).

A “database” is a collection of data points and data attributesassociated with each data point. Thus, a “data points, derived data, anddata attributes database” is a database comprising data pointscollected, e.g. from an x-ray image, data derived from the original datapoints and the data attributes associated with those data points or thederived data. A database may be limited to data points comprisingmeasurements of one or more levels; those data points may further becollected from one or more subjects. For example, one data pointdatabase may be created and the information in the database related to asecond database of attributes. Such combinations of one or moredatabases are within the skill of one of ordinary skill in the art inview of the teachings of the present specification. A “data warehouse”is another term for database. The term data warehouse is typicallyapplied to large databases.

“Formulation” of a database comprises collecting data points, inputtingthose data points into a desired database format, and associatingvarious attributes with each data point according to the particularformat employed. A wide variety of software exists which provides ameans for inputting data points, and associating the data points withdata attributes, such as Excel® (Microsoft® Corporation, Seattle, Wash.)spreadsheet software, Quattro® (Corel Inc., Ottawa, Canada) spreadsheetsoftware, Microsoft Access 2000® (Microsoft) software, Oracle® (OracleInc., Redwood Shores, Calif.) software, as well as other database anddata warehousing software.

“Manipulation” of a database refers to a variety of processes, e.g.,selecting, sorting, sifting, aggregating, clustering, modeling,exploring, and segmenting data points using various data attributes ortags associated with the data points. Available systems for generatingdatabases and manipulating the resulting databases include but are notlimited to Sybase® (Sybase Systems, Emeryville, Calif.), Oracle® (OracleInc., Redwood Shores, Calif.), and Sagent Design Studio® (SagentTechnologies Inc., Mountain View, Calif.) systems software. Further,statistical packages and systems for data analysis and data mining arealso available. Illustrative examples include SAS® (SAS Institute Inc.,Cary, N.C.) and SPSS® (SPSS Inc., Chicago, Ill.) systems software.

“Data mining” refers to the process of selecting, exploiting, modeling,etc., large amounts of data to uncover previously unknown trends,patterns, and relationships within and among various data points anddata attributes.

“Data aggregation” and “data clustering” refers to the process ofgrouping data points on the basis of one or more common attributes.Conversely, “data segmentation” refers to the process of differentiatingdata into discrete groups on the basis of one or more attributes.

General Overview

Methods and compositions useful in analyzing x-ray images are described.In particular, the invention includes methods of obtaining and/orderiving information from an x-ray image in network environment.Additionally, the present invention relates to the provision of accuratecalibration phantoms for X-ray systems and methods of using thesecalibration phantoms. Typically, the calibration phantom is formed of amaterial that simulates the properties of human bone tissue and isprovided in an x-ray assembly such that improved accuracy and precisionin the quantification of calcium, bone mass and bone density usingconventional X-ray equipment is achieved.

Advantages of the present invention include, but are not limited to, (i)providing fast, centralized networks for the analysis of x-ray images,particularly analysis of x-rays for bone mineral density; (ii) providingaccessible and reliable means for analyzing x-rays; (iii) providingaccurate calibration phantoms; (iv) providing accurate calibrationphantoms that can be readily used with standard x-ray technology; and(v) providing methods and materials for making these network-enabledtechniques and devices.

Database Formulation

The method of formulating data points, derived data, and data attributesdatabase according to the present invention may comprise the following:(1) the collection of data points, said data points comprisinginformation obtained from an x-ray image, for example, bone mineraldensity information; and (2) the association of those data points withrelevant data point attributes. The method may further comprise (3)determining derived data points from one or more direct data points and(4) associating those data points with relevant data point attributes.The method may also comprise (5) collection of data points using aremote computer whereby said remote computer operates in a networkenvironment.

In preferred embodiments, the information is obtained from an x-rayimage, for example of an anatomical structure or of a non-livingstructure. X-ray images can be acquired at a local site using knowntechniques. If the x-ray image was captured using conventional x-rayfilm, the data points (information) of the x-ray image can be digitizedusing a scanning device. The digitized x-ray image information can thenbe transmitted over the network, e.g. the Internet, into a remotecomputer or server. If the x-ray image was acquired using digitalacquisition techniques, e.g. using phosphorus plate systems or seleniumor silicon detector systems, the x-ray image information is alreadyavailable in digital format. In this case the image can be transmitteddirectly over the network, e.g. the Internet. The information can alsobe compressed and/or encrypted prior to transmission. Transmission canalso be by other methods such as fax, mail or the like.

Data Points

Thus, the methods of formulating data points, derived data, and dataattributes database that forms an aspect of the present invention beginswith the collection of data sets of measurement values, for examplemeasurements of bone mineral density from x-ray images. Records may beformulated in spreadsheet-like format, for example including dataattributes such as date of x-ray, patient age, sex, weight, currentmedications, geographic location, etc. The database formulation methodof the present invention may further comprise the calculation of derivedor calculated data points from one or more acquired data points. Avariety of derived data points may be useful in providing informationabout individuals or groups during subsequent database manipulation, andare therefore typically included during database formulation. Deriveddata points include, but are not limited to the following: (1) maximumbone mineral density, determined for a selected region of bone or inmultiple samples from the same or different subjects; (2) minimum bonemineral density, determined for a selected region of bone or in multiplesamples from the same or different subjects; (3) mean bone mineraldensity, determined for a selected region of bone or in multiple samplesfrom the same or different subjects; (4) the number of measurements thatare abnormally high or low, determined by comparing a given measurementdata point with a selected value; and the like. Other derived datapoints will be apparent to persons of ordinary skill in the art in lightof the teachings of the present specification. The amount of availabledata and data derived from (or arrived at through analysis of) theoriginal data provide provides an unprecedented amount of informationthat is very relevant to management of bone related diseases such asosteoporosis. For example, by examining subjects over time, the efficacyof medications can be assessed.

Measurements and derived data points are collected and calculated,respectively, and may be associated with one or more data attributes toform a database.

Data attributes can be automatically input with the x-ray image and caninclude, for example, chronological information (e.g., DATE and TIME).Other such attributes may include, but are not limited to, the type ofx-ray imager used, scanning information, digitizing information and thelike. Alternatively, data attributes can be input by the subject and/oroperator, for example subject identifiers, i.e. characteristicsassociated with a particular subject. These identifiers include but arenot limited to the following: (1) a subject code (e.g., a numeric oralpha-numeric sequence); (2) demographic information such as race,gender and age; (3) physical characteristics such as weight, height andbody mass index (BMI); (4) selected aspects of the subject's medicalhistory (e.g., disease states or conditions, etc.); and (5)disease-associated characteristics such as the type of bone disorder, ifany; the type of medication used by the subject. In the practice of thepresent invention, each data point would typically be identified withthe particular subject, as well as the demographic, etc. characteristicof that subject.

Other data attributes will be apparent to persons of ordinary skill inthe art in light of the teachings of the present specification.

Storage of Data Sets and Association of Data Points with Relevant DataAttributes

A number of formats exist for storing data sets and simultaneouslyassociating related attributes, including but not limited to (1)tabular, (2) relational, and (3) dimensional. In general the databasescomprise data points, a numeric value which correspond to physicalmeasurement (an “acquired” datum or data point) or to a single numericresult calculated or derived from one or more acquired data points thatare obtained using the various methods disclosed herein. The databasescan include raw data or can also include additional related information,for example data tags also referred to as “attributes” of a data point.The databases can take a number of different forms or be structured in avariety of ways.

The most familiar format is tabular, commonly referred to as aspreadsheet. A variety of spreadsheet programs are currently inexistence, and are typically employed in the practice of the presentinvention, including but not limited to Microsoft Excel spreadsheetsoftware and Corel Quattro spreadsheet software. In this format,association of data points with related attributes occurs by entering adata point and attributes related to that data point in a unique row atthe time the measurement occurs.

Further, rational, relational (Database Design for Mere Mortals, byMichael J. Hernandez, 1997, Addison-Wesley Pub. Co., publisher; DatabaseDesign for Smarties, by Robert J. Muller, 1999, Morgan KaufmannPublishers, publisher; Relational Database Design Clearly Explained, byJan L. Harrington, 1998, Morgan Kaufmann Publishers, publisher) anddimensional (Data-Parallel Computing, by V. B. Muchnick, et al., 1996,International Thomson Publishing, publisher; Understanding FourthDimensions, by David Graves, 1993, Computerized Pricing Systems,publisher) database systems and management may be employed as well.

Relational databases typically support a set of operations defined byrelational algebra. Such databases typically include tables composed ofcolumns and rows for the data included in the database. Each table ofthe database has a primary key, which can be any column or set ofcolumns, the values for which uniquely identify the rows in a table. Thetables in the database can also include a foreign key that is a columnor set of columns, the values of which match the primary key values ofanother table. Typically, relational databases also support a set ofoperations (e.g., select, join and combine) that form the basis of therelational algebra governing relations within the database.

Such relational databases can be implemented in various ways. Forinstance, in Sybase® (Sybase Systems, Emeryville, Calif.) databases, thetables can be physically segregated into different databases. WithOracle® (Oracle Inc., Redwood Shores, Calif.) databases, in contrast,the various tables are not physically separated, because there is oneinstance of work space with different ownership specified for differenttables. In some configurations, databases are all located in a singledatabase (e.g., a data warehouse) on a single computer. In otherinstances, various databases are split between different computers.

It should be understood, of course, that the databases are not limitedto the foregoing arrangements or structures. A variety of otherarrangements will be apparent to those of skill in the art.

Database Manipulation

Databases formulated using the methods of the present invention areuseful in that they can be manipulated, for example, using a variety ofstatistical analyses, to produce useful information. The databases ofthe present invention may be generated, for example, from data collectedfor an individual or from a selected group of individuals over a definedperiod of time (e.g., days, months or years), from derived data, andfrom data attributes.

The present invention further relates to a method for manipulating datapoints, derived data, and data attributes database in order to provide auseful result, said method comprising providing data points, deriveddata, and data attributes database, and manipulating and/or analyzingthe database.

For example, data sets may be aggregated, sorted, selected, sifted,clustered and segregated by means of the attributes associated with thedata points. A number of database management systems and data miningsoftware programs exist which may be used to perform the desiredmanipulations.

Relationships in the database can be directly queried and/or the dataanalyzed by statistical methods to evaluate the information obtainedfrom manipulating the database.

For example, a distribution curve can be established for a selected dataset, and the mean, median and mode calculated therefor. Further, dataspread characteristics, e.g. variability, quartiles and standarddeviations can be calculated.

The nature of the relationship between a particular variable and bonemineral density levels can be examined by calculating correlationcoefficients. Useful methods for doing so include but are not limited tothe following: Pearson Product Moment Correlation and Spearman RankOrder Correlation.

Analysis of variance permits testing of differences among sample groupsto determine whether a selected variable has a discernible effect on theparameter being measured.

Non-parametric tests may be used as a means of testing whethervariations between empirical data and experimental expectancies areattributable merely to chance or to the variable or variables beingexamined. These include the Chi Square test, the Chi Square Goodness ofFit, the 2×2 Contingency Table, the Sign Test, and the Phi CorrelationCoefficient.

There are numerous tools and analyses available in standard data miningsoftware that can be applied to the analysis of the databases of thepresent invention. Such tools and analyses include, but are not limitedto, cluster analysis, factor analysis, decision trees, neural networks,rule induction, data driven modeling, and data visualization. Some ofthe more complex methods of data mining techniques are used to discoverrelationships that are more empirical and data-driven, as opposed totheory-driven, relationships.

Exemplary data mining software that can be used in analysis and/orgeneration of the databases of the present invention includes, but isnot limited to: Link Analysis (e.g., Associations analysis, SequentialPatterns, Sequential time patterns and Bayes Networks); Classification(e.g., Neural Networks Classification, Bayesian Classification,k-nearest neighbors classification, linear discriminant analysis, Memorybased Reasoning, and Classification by Associations); Clustering (e.g.,k-Means Clustering, demographic clustering, relational analysis, andNeural Networks Clustering); Statistical methods (e.g., Means, Std dev,Frequencies, Linear Regression, non-linear regression, t-tests, F-test,Chi2 tests, Principal Component Analysis, and Factor Analysis);Prediction (e.g., Neural Networks Prediction Models, Radial BasedFunctions predictions, Fuzzy logic predictions, Times Series Analysis,and Memory based Reasoning); Operating Systems; and Others (e.g.,Parallel Scalability, Simple Query Language functions, and C++ objectsgenerated for applications). Companies that provide such softwareinclude, for example, the following: Adaptative Methods Group at UTS(UTS City Campus, Sydney, NSW 2000), CSI®, Inc., (Computer ScienceInnovations, Inc. Melbourne, Fla.), IBM® (International BusinessMachines Corporation, Armonk, N.Y.), Oracle® (Oracle Inc., RedwoodShores, Calif.) and SAS® (SAS Institute Inc., Cary, N.C.).

These methods and processes may be applied to the databases of thepresent invention, for example, databases comprising, x-ray image datasets, derived data, and data attributes.

For a general discussion of statistical methods applied to dataanalysis, see Applied Statistics for Science and Industry, by A. Romano,1977, Allyn and Bacon, publisher.

Hardware/Software and System Considerations

A. Hardware/Software

Various computer systems, typically comprising one or moremicroprocessors, can be used to store, retrieve, and analyze informationobtained according to the methods described herein. The computer systemcan be as simple as a stand-alone computer that is not networked toother computers, provided the system has a form of data storage, forexample disk drives, removable disk storage, for example ZIP® drives(Iomega Corporation, Roy, Utah), optical medium (e.g., CD-ROM), magnetictape, solid-state memory, and/or bubble memory. Alternatively, thecomputer system can include a networked computer system in which acomputer is linked to one or more additional computers, for example anetwork server. The networked system can be an intranet system and/or asystem linked to other computers via the Internet. Thus, the computersystems can be Internet-based systems or non-Internet based systems.

In addition, devices such as the Personal Digital Assistants (PDA), forexample Palm Pilot™ (Palm Inc., Santa Clara, Calif.) or Handspring™Visor™ (Handspring, Inc., Mountain View, Calif.) and Pocket PCs (PPC),for example Casio® EM500 Multimedia Cassiopeia Pocket PC (Casio Inc.,Dover, N.J.) or Compaq® iPAQ™ (Compaq Computer Corporation, Houston,Tex.) can be used to store and retrieve patient database information.The PDA or PPC can be a simple stand-alone device that is not networkedto other computers, provided the device has a form of data storage, forexample solid-state memory, SD (secure digital) and MMC (multimediacard) cards. Alternatively, the PDA or PPC can be attached to a networkin which the unit is linked to one or more computers, for example anetwork server or PC. The networked PDA or PPC can be an intranet systemand/or a system linked to computers via the Internet. Thus, the PDA orPPC systems can be Internet attached systems or non-Internet attachedsystems.

For example, information regarding x-ray images and the parameters thatwere used to acquire the x-ray image (e.g., acquisition parameters) canbe transmitted with the image over a local or long-distance network. Theimage acquisition parameters can be transmitted simultaneous with theimage or before or after the image transmission over the network. Imageacquisition parameters that can be transmitted in this fashion includebut are not limited to x-ray tube voltage settings, energy settings,x-ray tube current, film-focus distance, object-film distance,collimation, focal spot, spatial resolution, filter settings, etc. Theseparameters can be entered manually into a data registration sheet ordatabase that can be transmitted before, after or simultaneous with thex-ray images. Alternatively, at least some of these parameters can betransmitted automatically, while others that may be kept constantbetween different patients can be stored either at the local site or onthe network.

Thus, transmission of the x-ray acquisition parameters before, after orsimultaneous with the x-ray image over the network can be used toimprove the accuracy of quantitative measurements from x-ray images. Forexample, information on the density of an anatomic structure or anon-living object included on the x-ray image can be derived moreaccurately, when the x-ray image acquisition parameters are known.

The software can be installed in a PC, a Silicon Graphics, Inc. (SGI)computer or a Macintosh computer.

B. Stand-alone System

Connection to a central network (e.g., the Internet) can be made eitherdirectly, or via serial interface adapter. For example, a directconnection could be made if the readout device had wireless capability;alternately, a connection through a SIA or other sort of docking stationbetween the device and the network.

In some instances, a computer system includes a computer having anIntel® Pentium® microprocessor (Intel Corporation, Santa Clara, Calif.)that runs the Microsoft® WINDOWS® Version 3.1, WINDOWS95®, WINDOWS98®,or WINDOWS2000® operating system (Microsoft Corporation, Redmond,Wash.). Of course other microprocessors such as the ATHLON™microprocessor (Advanced Micro Devices, Inc., Sunnyvale, Calif.) and theIntel® CELERON® and XEON® microprocessors can be utilized. The methodsand systems can also include other operating systems, for example, UNIX,LINUX, Apple MAC OS 9 and OS X (Apple, Cupertino, Calif.), PalmOS® (PalmInc., Santa Clara, Calif.), Windows® CE 2.0 or Windows® CE Professional(Microsoft Corporation, Redmond, Wash.) without departing from the scopeof the present invention. Also typically included is the storage media,for example disk drive, removable disk storage, CD-ROM, required tostore and retrieve patient database information.

Communication with a computer system can be achieved using a standardcomputer interface, for example a serial interface or Universal SerialBus (USB) port. Standard wireless interfaces, for example radiofrequency (RF) technology—IEEE 802.11 and Bluetooth, and/or infraredtechnologies can also be used. The data can be encoded in the standardmanner, for example American Standard Code for Information Interchange(ASCII) format—a standard seven-bit code that was proposed by ANSI in1963, and finalized in 1968. ASCII is the common code for microcomputerequipment.

The computer system can store the information, for example into adatabase, using a wide variety of existing software that provides ameans for inputting data points, and associating the data points withdata attributes. Available systems for generating databases andmanipulating the resulting databases include but are not limited toExcel® (Microsoft® Corporation, Seattle, Wash.) spreadsheet software,Quattro® (Corel Inc., Ottawa, Canada), Sybase® (Sybase Systems,Emeryville, Calif.), Oracle® (Oracle Inc., Redwood Shores, Calif.), andSagent Design Studio® (Sagent Technologies Inc., Mountain View, Calif.)systems software. Further, statistical packages and systems for dataanalysis and data mining are also available (see above). Illustrativeexamples include but are not limited to SAS® (SAS Institute Inc., Cary,N.C.) and SPSS® (SPSS Inc., Chicago, Ill.). The database can be recordedon, for example a disk drive—internal or external to the system, aRead/Write CD-ROM drive, a tape storage system, solid-state memory orbubble memory, an SD or MMC. In addition to saving the data in adatabase, the information can be forwarded to an auxiliary readoutdevice such as a display monitor.

C. Networked System

Networked computer systems are also suitable for performing the methodsof the present invention. A number of network systems can be used, forexample a local area network (LAN) or a wide area network (WAN). Thenetwork computer system includes the necessary functionality forforwarding the data in established formats, for example Ethernet orToken Ring Packets or Frames, HTML-formatted data, or WAN digital oranalog protocols, in combination with any parameter information, forexample Destination Address, or Cyclic Redundancy Check (CRC). CRC is apowerful and easily implemented technique to obtain data reliability.The CRC technique is used to protect blocks of data called Frames. Usingthis technique, the transmitter appends an extra n-bit sequence to everyframe called Frame Check Sequence (FCS). The FCS holds redundantinformation about the frame that helps the transmitter detect errors inthe frame. The CRC is one of the most used techniques for errordetection in data communications into a format suitable for transmissionacross a transmission line for delivery to a database server. Further,the network system may comprises the necessary software and hardware toreceive the data from the readout device, store the data, process thedata, display the data in a variety of ways, and communicate back to thereadout device as well as to allow communication among a variety ofusers and between these users to the readout device.

The networked computer system, for example an Ethernet, Token Ring orFDDI network, can be accessed using a standard network interface card(NIC), for example a 3Com® EtherLink® NIC (3Com, Inc, Santa Clara,Calif.) which provide network connections over UTP, coaxial, orfiber-optic cabling or an Intel® PRO/100 S Desktop Adapter (IntelCorporation, Santa Clara, Calif.) or using a standard remote accesstechnology, for example a modem using a plain old telephone system(POTS) line, or a xDSL router connected to a digital subscriber lines(DSL), or a cable modem. Additionally, the networked computer system canbe connected to the LAN using a standard wireless interface, for exampleradio frequency (RF) technology—IEEE 802.11 and Bluetooth.

The networked computer system would have the same capability of storingdata, as the stand-alone system, onto a storage media, for example adisk drive, tape storage, or CD-ROM. Alternatively, the networkedcomputer system would be able to transfer data to any device connectedto the networked computer system for example a medical doctor or medicalcare facility using standard e-mail software, a central database usingdatabase query and update software (e.g., a data warehouse of datapoints, derived data, and data attributes obtained from a large numberof subjects). Alternatively, a user could access from a doctor's officeor medical facility, using any computer system with Internet access, toreview historical data that may be useful for determining treatment.

If the networked computer system includes a World Wide Web application,the application includes the executable code required to generatedatabase language statements, for example, SQL statements. Suchexecutables typically include embedded SQL statements. The applicationfurther includes a configuration file that contains pointers andaddresses to the various software entities that are located on thedatabase server in addition to the different external and internaldatabases that are accessed in response to a user request. Theconfiguration file also directs requests for database server resourcesto the appropriate hardware, as may be necessary if the database serveris distributed over two or more different computers.

Usually each networked computer system includes a World Wide Web browserthat provides a user interface to the networked database server. Thenetworked computer system is able to construct search requests forretrieving information from a database via a Web browser. With access toa Web browser users can typically point and click to user interfaceelements such as buttons, pull down menus, and other graphical userinterface elements to prepare and submit a query that extracts therelevant information from the database. Requests formulated in thismanner are subsequently transmitted to the Web application that formatsthe requests to produce a query that can be used to extract the relevantinformation from the database.

When Web-based applications are utilized, the Web application accessesdata from a database by constructing a query in a database language suchas Sybase or Oracle SQL which is then transferred to a relationaldatabase management system that in turn processes the query to obtainthe pertinent information from the database.

Accordingly, in one aspect the present invention describes a method ofproviding data on x-ray images on a network, for example the Internet,and methods of using this connection to provide real-time and delayeddata analysis. The central network can also allow access by thephysician to a subject's data. Similarly, an alert could be sent to thephysician if a subject's readings are out of a predetermined range, etc.The physician can then send advice back to the patient via e-mail or amessage on a web page interface. Further, access to the entire databaseof data from all subjects may be useful to the for statistical orresearch purposes. Appropriate network security features (e.g., for datatransfer, inquiries, device updates, etc.) are of course employed.

Further, a remote computer can be used to analyze the x-ray that hasbeen transmitted over the network automatically. For example, x-raydensity information or structural information about an object can begenerated in this fashion. X-ray density information can, for example,be bone mineral density. If used in this fashion, the test can be usedto diagnose osteoporosis (See, FIG. 1).

D. Graphical User Interface

In certain of the computer systems, an interface such as an interfacescreen that includes a suite of functions is included to enable users toeasily access the information they seek from the methods and databasesof the invention. Such interfaces usually include a main menu page fromwhich a user can initiate a variety of different types of analyses. Forexample, the main menu page for the databases generally include buttonsfor accessing certain types of information, including, but not limitedto, project information, inter-project comparisons, times of day,events, dates, times, ranges of values, etc.

E. Computer Program Products

A variety of computer program products can be utilized for conductingthe various methods and analyses disclosed herein. In general, thecomputer program products comprise a computer-readable medium and thecode necessary to perform the methods set forth supra. Thecomputer-readable medium on which the program instructions are encodedcan be any of a variety of known medium types, including, but notlimited to, microprocessors, floppy disks, hard drives, ZIP drives, WORMdrives, magnetic tape and optical medium such as CD-ROMs.

For example, once an x-ray is transmitted via a local or long-distancecomputer network and the data on the x-ray received by a remote computeror a computer connected to the remote network computer, an analysis ofthe morphology of the object can be performed, for example usingsuitable computer programs. This analysis of the object's morphology canoccur in two-dimensions, although it is also possible inthree-dimensions, in particular when x-ray images have been acquiredthrough the anatomic object using multiple different x-ray transmissionangles. For example, in imaging osseous structures, such morphologicalanalysis of the transmitted x-ray image can be used to measureparameters that are indicative or suggestive of bone loss or metabolicbone disease. Such parameters include all current and future parametersthat can be used to evaluate osseous structures. For example, suchparameters include, but are not limited to, trabecular spacing,trabecular thickness and intertrabecular space.

Information on the morphology or 2D or 3D morphology of an anatomicstructure can be derived more accurately, when x-ray image acquisitionparameters such as spatial resolution are known. Other parameters suchas the degree of cone beam distortion can also be helpful in thissetting.

As noted above, an x-ray image can be transmitted from a local site intoa remote server and the remote server can perform an automated analysisof the x-ray. Further, the remote server or a computer connected to theremote server can then generate a diagnostic report. Thus, in certainembodiments, a computer program (e.g., on the remote server or on acomputer connected to the remote server) can generate charges for thediagnostic report. The remote server can then transmit the diagnosticreport to a physician, typically the physician who ordered the test orwho manages the patient. The diagnostic report can also be transmittedto third parties, e.g. health insurance companies. Such transmission ofthe diagnostic report can occur electronically (e.g. via e-mail), viamail, fax or other means of communication. All or some of thetransmitted information (e.g., patient identifying information) can beencrypted to preserve confidentiality of medical records.

Typically, one or more computer programs capable of generating billswill also be employed, for example a bill-making program on the remoteserver. The charges on the bill will typically follow general medicalreimbursement guidelines. The bill can be transmitted electronically(e.g. via e-mail), via mail, fax or other means of communication.Splitting of fees can also be performed by these programs, for examplewhere a percentage of the fee for the diagnostic test is transferred tothe physician responsible for interpreting the test, a percentage of thefee for the diagnostic test is transferred to the agency, e.g. ahospital, x-ray clinic, women's clinic, dentist's office acquiring thex-ray image, and a percentage of the fee for the diagnostic test istransferred to the entity responsible for the extraction of x-rayinformation and automated analysis. Such fees can contain a professionaland a technical component. Bills can be transmitted simultaneously withthe transmission of the results of the automated network based analysisor can be transmitted after the report is sent. Similarly, payment canbe collected using any suitable medium, for example payment by creditcard over the Internet or by mail.

Calibration Phantoms

Although a wealth of information can be obtained from x-ray imagesalone, it is highly preferred that the networked x-ray images includeaccurate reference markers, for example calibration phantoms forassessing bone mineral density of any given x-ray image. Thus, incertain aspects, the current invention provides for methods and devicesthat allow accurate quantitative assessment of information contained inan x-ray such as x-ray density of an anatomic structure or morphology ofan anatomic structure in a network environment.

An x-ray image can be acquired using well-known techniques from anylocal site. For example, in certain aspects, 2D planar x-ray imagingtechniques are used. 2D planar x-ray imaging is a method that generatesan image by transmitting an x-ray beam through a body or structure ormaterial and by measuring the x-ray attenuation on the other side ofsaid body or said structure or said material. 2D planar x-ray imaging isdistinguishable from cross-sectional imaging techniques such as computedtomography or magnetic resonance imaging. If the x-ray image wascaptured using conventional x-ray film, the x-ray can be digitized usingany suitable scanning device. The digitized x-ray image is thentransmitted over the network, e.g. the Internet, into a remote computeror server. It will be readily apparent that x-ray images can also beacquired using digital acquisition techniques, e.g. using phosphorusplate systems or selenium or silicon detector systems, the x-ray imageinformation is already available in digital format. In this case theimage can be transmitted directly over the network, e.g. the Internet,or alternatively, it can be compressed prior to transmission.

In preferred embodiments, when an x-ray of an anatomic structure or anon-living object is acquired a calibration phantom is included in thefield of view. Any suitable calibration phantom can be used, forexample, one that comprises aluminum or other radio-opaque materials.U.S. Pat. No. 5,335,260 describes other calibration phantoms suitablefor use in assessing bone mineral density in x-ray images. Examples ofother suitable calibration reference materials can be fluid orfluid-like materials, for example, one or more chambers filled withvarying concentrations of calcium chloride or the like.

It will be readily apparent that a calibration phantom can containseveral different areas of different radio-opacity. For example, thecalibration phantom can have a step-like design, whereby changes inlocal thickness of the wedge result in differences in radio-opacity.Stepwedges using material of varying thickness are frequently used inradiology for quality control testing of x-ray beam properties. Byvarying the thickness of the steps, the intensity and spectral contentof the x-ray beam in the projection image can be varied. Stepwedges arecommonly made of aluminum, copper and other convenient and homogeneousmaterials of known x-ray attenuation properties. Stepwedge-like phantomscan also contain calcium phosphate powder or calcium phosphate powder inmolten paraffin.

Alternatively, the calibration reference may be designed such that thechange in radio-opacity is from periphery to center (for example in around, ellipsoid, rectangular of other shaped structure). As notedabove, the calibration reference can also be constructed as plurality ofseparate chambers, for example fluid filled chambers, each including aspecific concentration of a reference fluid (e.g., calcium chloride).

Whatever the overall shape of the calibration phantom, it is preferredthat at least one marker be present at a known density in the phantom.Presently, areas of the calibration phantom will often fail to appear onx-ray images. This is particularly true of areas at the highest andlowest density levels. Thus, it is often difficult to determine what thedensity is of any particular area of the calibration phantom. Thepresent invention solves this problem by ensuring that at least onegeometric shape is included in the calibration phantom at a position ofknown density. Any shape can be used including, but not limited to,squares, circles, ovals, rectangles, stars, crescents, multiple-sidedobjects (e.g., octagons), irregular shapes or the like, so long as theirposition is known to correlate with a particular density of thecalibration phantom. In preferred embodiments, the calibration phantomsdescribed herein are used in 2D planar x-ray imaging.

Since the density and attenuation of the calibration phantom are bothknown, the calibration phantom provides an external reference formeasuring the density of the anatomic structure or non-living object tobe measured.

For example, a wedge-shaped calibration phantom can provide referencemeasurements to express the density of an anatomic structure in terms ofthickness of the phantom material. For this purpose, a calibration curvedescribing the relationship between measured attenuation and materialthickness can be derived from the image of the phantom. For awedge-shaped calibration phantom with the length L and a linear changefrom a maximum thickness T to thickness 0, each point X in the image ofthe wedge at distance D from the thin end of the wedge results in apoint (T*L/D, G) of the calibration curve, where T*L/D is the thicknessof the wedge at X and G the attenuation at X.

A calibration wedge that results in a non-linear calibration curve canbe used if the radiograph has to be acquired such that both ends of thewedge cannot be properly identified, so that the distance D is unknown.If the shape of the expected entire calibration curve is known, the partof the curve that can be calculated from the identified regions of thecalibration wedge can be fitted to the expected curve. This way, theexact position on the wedge can be determined.

For a known attenuation of a particular anatomic structure, thecorresponding thickness value is determined with use of said calibrationcurve.

Furthermore, calibration curves for measurement units A and B that arecalculated with use of the same calibration phantom can be used totranslate a measurement from unit A into unit B. For example, bonemineral density can be assessed from a radiograph that also contains animage of an aluminum step wedge. Bone mineral density, which can then beexpressed in units of aluminum thickness. In order to translate thisinto units of calcium concentration, another calibration curve relatingunits of calcium concentration to aluminum thickness can be created fromanother radiographic image that contains the same aluminum step wedge aswell as samples of varying calcium concentration. Using this secondcalibration curve, values expressed in aluminum thickness can beconverted into units of calcium concentration. One of skill in the artwill easily recognize other applications for use of calibration phantomsin x-ray imaging in view of the teachings herein.

The calibration phantoms can be imaged before or after the x-ray imageis taken. Alternatively, the calibration phantom can be imaged at thesame time as the x-ray image. The calibration phantom can be physicallyconnected to an x-ray film and/or film holder. Such physical connectioncan be achieved using any suitable mechanical or other attachmentmechanism, including but not limited to adhesive, a chemical bond, useof screws or nails, welding, a Velcro™ strap or Velcro™ material and thelike. Similarly, a calibration phantom can be physically connected to adetector system or a storage plate for digital x-ray imaging using oneor more attachment mechanisms (e.g., a mechanical connection device, aVelcro™ strap or other Velcro™ material, a chemical bond, use of screwsor nails, welding and an adhesive).

The attachment may be permanent or temporary and the calibration phantomcan be integral (e.g., built-in) to the film, film holder and/ordetector system or can be attached or positioned permanently ortemporarily appropriately after the film and/or film holder is produced.Thus, the calibration phantom can, be designed for single-use (e.g.,disposable) or for multiple uses with different x-ray images. Thus, incertain embodiments, the calibration phantom is reusable and,additionally, can be sterilized between uses. Integration of acalibration phantom can be achieved by including a material of knownx-ray density between two of the physical layers of the x-ray film.Integration can also be achieved by including a material of known x-raydensity within one of the physical layers of the x-ray film.Additionally, the calibration phantom can be integrated into the filmcover. A calibration phantom or an external standard can also beintegrated into a detector system or a storage plate for digital x-rayimaging. For example, integration can be achieved by including amaterial of known x-ray density between two of the physical layers ofthe detector system or the storage plate. Integration can also beachieved by including a material of know x-ray density within one of thephysical layers of the detector system or the storage plate.

In certain embodiments, for example those embodiments in which thecalibration phantom is temporarily attached to the x-ray assembly,cross-hairs, lines or other markers may be placed on the apparatus asindicators for positioning of the calibration phantom. These indicatorscan help to ensure that the calibration phantom is positioned such thatit doesn't project on materials that will alter the apparent density inthe resulting image.

FIG. 2 and FIG. 3 show two examples of dental x-ray film holders thatcan be designed to include a calibration phantom. (See, also U.S. Pat.Nos. 5,001,738 and 4,251,732). It should be noted that FIG. 2 and FIG. 3depict only two shapes of any number of shapes suitable for x-ray filmholders. Furthermore, although illustrated with respect to dental x-rayfilm and/or film holders, it will be readily apparent that calibrationphantoms as described herein can be included in any type of x-ray filmand/or film holder.

FIG. 2 shows a film packet (11) for holding x-ray film. Film packet (11)is within a bite wing film holder (10) that has a bite tab (12)extending perpendicular from the film holder (11). The opening (13)allows alignment on a patient's teeth. As shown, the bite tab (12) has agenerally square shape. A curved cutaway portion (20) along one edge canbe included to allow better aiming of the x-ray tube. A calibrationphantom can be positioned in any suitable location on the holder or filmfollowing the teachings described herein. In preferred embodiments, itis highly desirable that the calibration phantom be positioned so itdoesn't project on structures or materials that will alter the apparentdensity of the calibration phantoms. It is also desirable that thecalibration phantom includes a marker (e.g., geometric pattern) at aknown density to increase the accuracy of the phantom as an externalstandard. Accordingly, the calibration phantom can be positioned wherethe bite wing (12) meets the film holder (11), for example near the bend(18) or along the area (8) created where the bite wing (12) meets thefilm holder (11). Such careful positioning ensures that the calibrationphantom will appear in the x-ray image between the teeth and, therefore,will be more accurate than if bone (e.g., jaw) or teeth. It will bereadily apparent that the area containing the calibration phantom can bemade slightly thicker to ensure that the calibration phantom does notproject on bone tissue in the x-ray image.

Referring now to FIG. 3, another exemplary x-ray film holder (10)consists of one-piece construction with an extension (2) for alignmentof the x-ray beam, and manual positioning of a bite platform (14) andfilm holding slotted portions (16), (48) and (20). The extension (2) isconnected to platform (14) at a “T” shaped area (22). Film holdingslotted portion (16) is perpendicularly connected to platform (14) at(24) and comprises side walls (26) and slot (36) which are used tosupport film (30), for example in the upper right posterior exposureposition as shown in FIG. 3. A calibration phantom (e.g., stepwedge,fluid chambers, etc.) can again be permanently or temporarily positionedin any suitable location, preferably so that it appears in the x-rayimage but does not project on or with materials or structures that willalter the apparent density of the calibration references in the x-rayimage. Non-limiting examples of such suitable positions include in filmholder portions (16, 48, 20), for example within or on the surface ofclosed portion (50, 60) of the film holders. Other suitable locationscan be readily determined following the teachings of the presentspecification.

FIG. 4 shows another exemplary embodiment in which a calibration phantom(100) is attached to a dental x-ray film holder (200). The film holder(200) with the film (105) is positioned such that the calibrationphantom (100), the teeth (300) and the jaw bone (400) project onto thefilm.

FIG. 5 shows an embodiment in which the calibration phantom (101) isattached (permanently or temporarily) to the x-ray film (500).

FIG. 6 shows an embodiment in which a calibration phantom (120)integrated into the film cover (600) that protects the film (205) fromexposure to light.

FIG. 7 shows an embodiment in which a calibration phantom (150) isintegrated into a detector system (77). The calibration phantom can beintegrated between individual or rows of detectors, or on top orunderneath the detectors using any suitable permanent or temporaryattachment means (e.g., velcro, adhesive, etc.).

FIG. 8 shows one example of measurement sites (arrows from 108) in adental x-ray that can be used as intrinsic standards to calibrate theimage. Teeth (301) and bone (42) are also depicted.

FIG. 9 shows another example of measurement sites (arrows from 108) in adental x-ray that can be used as intrinsic standards to calibrate theimage. Teeth (320) and bone (410) are also depicted.

Any of the calibration phantom-containing assemblies described hereincan be used in methods of analyzing and/or quantifying bone mineraldensity in an x-ray image. The methods generally involve simultaneouslyimaging or scanning the calibration phantom and another material (e.g.,bone tissue from a subject) for the purpose of quantifying the densityof the imaged material (e.g., bone mass). A “subject” preferably refersto an animal, for example a mammal such as a human. As used herein theterm “patient” refers to a human subject.

Thus, under the method of the present invention, the calibration phantomis preferably imaged or scanned simultaneously with the individualsubject, although the invention allows for non-simultaneous scanning ofthe phantom and the subject. Methods of scanning and imaging structuresby radiographic technique are well known. By placing the calibrationphantom in the x-ray beam with the subject, reference calibrationsamples allow corrections and calibration of the absorption propertiesof bone. When the phantom is imaged or scanned simultaneously with eachsubject, the variation in x-ray beam energy and beam hardening arecorrected since the phantom and the subject both see the same x-ray beamspectrum. Each subject, having a different size, thickness,muscle-to-fat ratio, and bone content, attenuate the beam differentlyand thus change the effective x-ray beam spectrum. It is necessary thatthe bone-equivalent calibration phantom be present in the same beamspectrum as the subject's bone to allow accurate calibration.

X-ray imaging assemblies that are currently in use do not take intoaccount the position of the calibration phantom in relation to thestructures being imaged. Thus, when included in known assemblies,calibration phantom(s) are often positioned such that they project onmaterials or structures (e.g., bone) that alter apparent density of thecalibration phantom in the resulting x-ray image. Clearly, thisalteration in apparent density will affect the accuracy of thecalibration phantom as a reference for determining bone mineral density.Therefore, it is an object of the invention to provide methods in whichthe calibration phantom projects free of materials or structures thatwill alter the apparent density of the reference. In the context ofdental x-rays, for instance, the methods described herein ensure thatthe calibration phantom projects free of bone (e.g., teeth, jaw) tissue.As described above with reference to FIGS. 2 and 3, this can beaccomplished in a variety of ways, for example, positioning thecalibration phantom in the x-ray film or in the x-ray film holder suchthat it will appear between the teeth in the dental x-ray.

The calibration phantom materials and methods of the present inventionare suitable for use in both conventional radiography systems andcomputed tomography (CT) systems. In conventional radiography systems,for example, a stepwedge phantom can be fabricated from a matrixcontaining a desired concentration of reference material in varyingthicknesses is used. In addition, the calibration phantoms as describedherein can readily be configured to be small enough and thin enough tobe placed inside the mouth, and the method of the present invention canbe used to quantify bone mass using standard dental x-ray systems, forexample by including temporary or permanent calibration phantoms indental x-ray film holders.

In other embodiments of the invention, information inherent in theanatomic structure or the non-living object can be used to estimate thedensity of selected regions of interest within the anatomic structure orthe non-living object. For example, since the x-ray density of muscle,fat, and air are known, the density of air surrounding an anatomicstructure or non-living object, the density of subcutaneous fat, and thedensity of muscle tissue can be used to estimate the density of aselected region of bone, for example within the distal radius.

Said information inherent in said anatomic structure can also becombined with information provided by the calibration phantom. Saidcombination can result in an improved accuracy of the calibration.

In another embodiment, a general calibration curve is created from anumber of reference images that contain a calibration phantom, forexample by calculating the average of the calibration curves for theindividual reference images. This general calibration curve is thensubsequently used to calibrate images that are acquired without acalibration phantom.

The invention also provides kits for obtaining information from x-rayimages, for example for obtaining information regarding bone mineraldensity from an x-ray. In certain embodiments, the kit comprises one ormore computer (e.g., software) programs, for example for receiving,analyzing and generating reports based on x-ray images. In furtherembodiments, the kits can include calibration phantoms, for examplecalibration phantoms integrated or attachable-to x-ray film and/or x-rayfilm holders.

All of these aspects of the invention can be practiced separately or incombination. Typically, the use of combinations of the embodimentslisted above is more advantageous. Further, although preferredembodiments of the subject invention have been described in some detail,it is understood that obvious variations can be made without departingfrom the spirit and the scope of the invention.

Experimental

Below are examples of specific embodiments for carrying out the presentinvention. The examples are offered for illustrative purposes only, andare not intended to limit the scope of the present invention in any way.

EXAMPLE 1 Calibration Phantom Integrated into Film Cover

The workflow presented herein constitutes one example for the use of acalibration phantom with the image acquisition. One skilled in the artwill readily recognize other ways to include a calibration phantom inthe acquisition process in order to normalize or standardize any form ofmeasurement made from the x-ray image.

In this example, the calibration phantom is integrated into the cover ofa dental x-ray film that protects it from exposure to light. The film isplaced into the film holder that is used to hold the film in thepatient's mouth. The film holder with the film is positioned inside thepatient's mouth in such a way that the calibration phantom is notobstructed from the x-ray beam by any structures such as teeth or thelips etc.

After acquisition of the image, the film is taken to the darkroom andthe cover with the calibration phantom is removed. The film is thenprocessed in the same way as a conventional dental x-ray film.

EXAMPLE 2 Transmission of X-Ray Image Including Image of CalibrationPhantom over a Network

This example describes one possible typical application of theinvention, in which a digitized x-ray image that includes the image of acalibration phantom is transmitted over a network. Similar applicationsof the invention can easily be recognized.

The x-ray image is acquired in such a way that the calibration phantomis projected onto the film. The film with the x-ray image and the imageof the calibration phantom is developed. Subsequently, the film isdigitized, for example using a flat-bed or slide film scanner, resultingin a digital image. The digital image, which includes the x-ray imageand the image of the calibration phantom, is then transmitted over anetwork to a remote computer. The remote computer performs one or moremeasurements using information from the x-ray image and/or the image ofthe calibration phantom.

EXAMPLE 3 Transmission of X-Ray Image Including Image AcquisitionParameters

The transmission of image data over a network can also include datadescribing the image acquisition parameters. After acquisition anddigitization of the x-ray image, the acquisition parameters are enteredinto the local computer system. These parameters can include, but arenot limited to, voltage settings, tube current, or film-focus distance.The image and acquisition parameter data are then transmitted over thenetwork to a remote computer.

At the remote computer, the image is analyzed. The acquisitionparameters can be used in this evaluation to improve the accuracy of themeasurements. The results can be sent back to the original location viaa digital network or by fax transmission. The results can also betransmitted to third parties.

EXAMPLE 4 Remote Analysis of X-Ray Image

This example describes a scenario of the invention in which an x-rayimage is acquired at a local site and transmitted to a remote site toperform an analysis. Variations of this example can easily berecognized.

After acquisition of the x-ray with a conventional x-ray machine thefilm is developed. Subsequently, the film is digitized, using, forexample, a commercial flat-bed scanner. The digitized image data istransmitted to a remote computer via, for example, a digital network ora phone line. At the remote computer, an automated analysis of the imageis performed. The results of this analysis can be sent back to the localcomputer. They can also be transmitted by a fax connection. The resultscan also be sent to a third party.

1. A method of generating a density calibration curve, comprising thesteps of (a) providing an assembly comprising an x-ray film holder;x-ray film and a wedge-shaped calibration phantom having length (L) andvarying thickness (T) along the length: (b) producing an x-ray image ofan anatomical structure, wherein the x-ray image comprises thecalibration phantom; (c) measuring attenuation at a multitude of pointsin the x-ray image of the calibration phantom, wherein each point is atknown distance from a selected part of the phantom; (d) measuringattenuation of at least one point of known density in the x-ray image ofthe anatomical structure; and (e) generating a calibration curve thatdescribes the relationship between attenuation measured in (c) and (d)and material thickness.
 2. The method of claim 1, further comprising thestep of translating the calibration curve describing thickness into acurve describing calcium concentration.
 3. The method of claim 2,wherein the calibration phantom comprises aluminum and the calibrationcurve describes aluminum thickness.
 4. A method of generating areference calibration curve, comprising the step of calculating theaverage of calibration curves obtained according to the method ofclaim
 1. 5. The method of claim 1, wherein the x-ray image is a dentalx-ray.
 6. The method of claim 1, wherein the calibration curve isgenerated in a network environment.
 7. A method of diagnosingosteoporosis comprising the step of analyzing an x-ray image obtained bythe method of claim 1, wherein if the bone mineral density is below areference standard, osteoporosis is diagnosed.
 8. A method of treatingosteoporosis comprising diagnosing osteoporosis according to the methodof claim 7 and administering one or more anti-resorptive agents or oneor more anabolic agents.
 9. The method of claim 1, wherein, in step (d),the at least one point of known density in the anatomical structure isin muscle, fat, or air.
 10. The method of claim 9, wherein the fat issubcutaneous fat.
 11. A method of generating a density calibrationcurve, comprising the steps of (a) providing an assembly comprising anx-ray film holder; x-ray film and a wedge-shaped calibration phantomhaving length (L) and varying thickness (T) along the length and whereinthe thickness of calibration phantom varies non-linearly along itslength; (b) producing an x-ray image of an anatomical structure, whereinthe x-ray image comprises the calibration phantom; (c) providing anexpected calibration curve for the non-linear calibration phantom; (d)measuring attenuation at a multitude of points in the x-ray image of thecalibration phantom; (e) measuring attenuation of at least one point ofknown density in the x-ray image of the anatomical structure: and (e)aligning the points measured in steps (d) and (e) with the expectedcalibration curve generated in step (c), thereby generating acalibration curve for the image.
 12. The method of claim 11, furthercomprising the step of translating the calibration curve describingthickness into a curve describing calcium concentration.
 13. The methodof claim 12, wherein the calibration phantom comprises aluminum and thecalibration curve describes aluminum thickness.
 14. A method ofgenerating a reference calibration curve, comprising the step ofcalculating the average of calibration curves obtained according to themethod of claim
 11. 15. The method of claim 11, wherein, in step (e),the at least one point of known density in the anatomical structure isin muscle, fat, or air.
 16. The method of claim 15, wherein the fat issubcutaneous fat.
 17. A method of generating a density calibrationcurve, comprising the steps of (a) generating a digital x-ray image ofan anatomic structure that includes a wedge-shaped calibration phantomhaving length (L) and varying thickness (T) along the length; (b)generating an expected calibration curve; and (c) measuring attenuationat a multitude of points in the x-ray image including the calibrationphantom; (d) measuring attenuation of at least one point of knowndensity in the x-ray image of the anatomical structure: and (e) aligningthe points measured in steps (c) and (d) with the expected calibrationcurve generated in step (b), thereby generating a calibration curve forthe image.
 18. The method of claim 17, further comprising the step oftranslating the calibration curve describing thickness into a curvedescribing calcium concentration.
 19. The method of claim 18, whereinthe calibration phantom comprises aluminum and the calibration curvedescribes aluminum thickness.